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1.
Medicine (Baltimore) ; 98(38): e17251, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567994

RESUMO

RATIONALE: Triple-negative breast cancer has a dismal prognosis, especially once it has spread to other organs, due to the lack of effective treatments available at this time. Finding an effective treatment for metastatic triple-negative breast cancer remains an unmet medical need. PATIENT CONCERNS: A 60-year-old woman was diagnosed with stage IIIC triple-negative breast cancer after undergoing a mastectomy. Her mastectomy was followed by adjuvant chemotherapy and radiation therapy. Approximately 1 year later, the patient presented with enlarging lymph nodes in her neck. A biopsy of a left supraclavicular lymph node was positive for recurrent disease. Positron emission tomography and computed tomography scans performed after the biopsy showed metabolic activity in the T6 vertebral body and the right level IIB lymph nodes. DIAGNOSES: The patient was diagnosed with recurrent metastatic triple-negative breast carcinoma with metastases to the bone and lymph nodes. INTERVENTIONS: The patient was treated with weekly metronomic chemotherapy, sequential chemotherapy regimens, and immunotherapy. OUTCOMES: The patient is now 68 years old and 7 years out from her diagnosis of metastatic disease. She achieved a complete response to her treatment and routine scans continue to show no evidence of recurrent disease. LESSONS: Utilizing sequential weekly metronomic chemotherapy regimens in combination with immunotherapy looks to be a promising treatment option for patients with metastatic triple-negative breast carcinoma. This is a second case where we were able to achieve long-term remission by using the above treatment strategy. These exciting results warrant further investigation of this treatment methodology. We hope that the treatment strategy described in this article can provide an outline for researchers and give patients with this disease more treatment options.


Assuntos
Neoplasias da Mama/terapia , Neoplasias de Mama Triplo Negativas/terapia , Administração Metronômica , Idoso , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Humanos , Mastectomia , Sobreviventes , Neoplasias de Mama Triplo Negativas/patologia
2.
Medicine (Baltimore) ; 98(40): e17370, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577739

RESUMO

The aims of this study were to explore the expression of hypoxia inducible factor-1α (HIF-1α) and c-myc protein in triple-negative breast cancer (TNBC) and its clinical prognostic significance, and to establish a prediction model for postoperative survival of TNBC based on nomogram.A total of 87 patients with TNBC at the Department of Breast Surgery, Beijing Chaoyang Hospital, Capital Medical University from January 2012 to December 2015 were enrolled in this study. Immunohistochemistry was performed to detect the expression of HIF-1α and c-myc protein in breast cancer tissues. Cox regression analyses were performed to explore the correlation between HIF-1α/c-myc expression and clinical pathological parameters as well as prognosis. Receiver-operating characteristic curve was generated for cox multivariate analysis. A nomogram was generated based on the cox multivariate analysis, and a calibration curve was prepared for the nomogram to evaluate the consistency between the predicted probability of the nomogram and the actual observed probability. The stability of nomogram model was validated with an external cohort including 39 TNBC patients.The positive expression rates of HIF-1α and c-myc protein in breast cancer tissues were 41.4% (36/87) and 55.2% (48/87), respectively. HIF-1α expression was significantly correlated with age, tumor diameter, histological grade, lymph node status, and tumor TNM stage; c-myc expression was significantly associated with tumor diameter, histological grade, lymph node status, and tumor TNM stage. Cox univariate and multivariate analyses showed that HIF-1α and c-myc protein expression, histological grade, lymph node status, and tumor TNM stage were the independent risk factors for postoperative survival in TNBC patients. The AUC of prediction model was 0.843 (0.809-0.887). The nomogram could predict the probability of 3-year disease-free survival according to each patient's condition. The calibration curve displayed good agreement of the predicted probability with the actual observed probability, indicating that the nomogram model had great value of prediction. The external validation indicated the prediction model had good stability.HIF-1α-positive expression, c-myc positive expression, histological grade III, lymph node positive, and TNM stage III tumors suggested that TNBC patients had a poor prognosis. This prediction model can be used to predict postoperative survival of TNBC.


Assuntos
Genes myc/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Fatores Etários , Biomarcadores Tumorais , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Neoplasias de Mama Triplo Negativas/cirurgia , Carga Tumoral
3.
Gene ; 720: 144088, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476404

RESUMO

BACKGROUND: Secretory leukocyte protease inhibitor (SPLI) was a secreted protein which belongs to a member of whey acidic protein four-disulfide core family. In breast cancer (BC) it may inhibit cell proliferation and promote cancer metastasis. In this study, a comprehensive bioinformatics analysis was performed to identify the expression and prognostic value of SLPI in breast cancer. METHODS: SLPI expression in breast cancer was analyzed in Oncomine online database, which was subsequently confirmed by quantitative PCR (qPCR) in 18 BC samples and western blotting in 26 BC samples. Breast cancer gene-expression miner v4.1 was used to access the expression level with clinicopathological parameters in breast cancer patients. The prognostic values of SLPI in breast cancer were evaluated using the PrognoScan database. RESULTS: Our results indicated that SLPI was downregulated in breast cancer than in normal tissues. SLPI expression was found to be negatively correlated with estrogen receptor (ER) and progesterone receptor (PR) status. SLPI expression level was decreased in negative basal-like status patients compared with positive basal-like status. Meanwhile, triple-negative breast cancer status positive correlated with SLPI. We confirmed a positive correlation between SLPI and interleukin 17 receptor B (IL17RB) express in breast cancer tissues via oncomine co-expression analysis. Ten proteins: Elastase, Granulin, Lipocalin, Defensin beta 103B, Defensin beta 103A, Tubulin, Heparin-binding EGF-like growth factor, Interleukin 6, Epidermal growth factor, Phospholipid scramblase 1 were determinate interactions with SLPI by STRING. CONCLUSION: SLPI could as a biomarker to predict the prognosis values of breast cancer. However, further comprehensive study and mining more evidence are needed to clarify our results.


Assuntos
Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Inibidor Secretado de Peptidases Leucocitárias/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
4.
Life Sci ; 234: 116783, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31442552

RESUMO

Breast cancer (BCa) is the most commonly diagnosed lethal cancer in women worldwide. Notch signaling pathway is directly linked to BCa recurrence and aggressiveness. Natural remedies are becoming a prime choice to overcome against cancer due to lesser side effect and cost-effectiveness. Bulbine frutescens (Asphodelaceae), a traditional medicinal plant in South Africa possess bioactive flavonoids and terpenoids. Polar (methanol) and non-polar (hexane) B. frutescens plant extracts were prepared. GC-MS analysis revealed the differential presence of secondary metabolites in both methanolic and hexane extracts. We hereby first time evaluated the anticancer potential of B. frutescens methanolic and hexane extract in triple-negative and luminal BCa cells. B. frutescens extracts significantly decreased cell viability (IC50 4.8-28.4 µg/ml) and induced cell cycle arrest at G1 phase in MDA-MB-231 and T47D cells as confirmed by spectrophotometry and flow cytometry technique. RT-PCR analysis of cell cycle (cyclin D1, CDK4, and p21) and apoptosis modulating genes (caspase 3, Bcl2 and survivin) revealed upexpression of p21, and caspase 3, and down expression of cyclin D1, CDK4, Bcl2 and survivin genes in extract-treated BCa cells. Fluorescence spectrophotometry and confocal microscopy showed B. frutescens induced nuclear morphology and mitochondrial integrity disruption, and increased reactive oxygen species production in MDA-MB-231 and T47D cells. Flow cytometric apoptosis analysis of B. frutescens extracts treated MDA-MB-231 cells showed ≈13% increase in early apoptotic population in comparison to non-treated cells. Dual-Luciferase Reporter assay confirmed notch promoter inhibitory activity of B. frutescens extracts. Moreover, RTPCR analysis showed down regulation of notch responsive genes (Hes1 and Hey1) at transcription levels in extract-treated BCa cells. Western Blot analysis showed increased procaspase 3 protein expression in extract-treated BCa cells. In all the assays methanolic extract showed better anti-cancer properties. Literature-based identification of methanol soluble phytochemicals in B. frutescens and in silico docking study revealed Bulbineloneside D as a potent ϒ-secretase enzyme inhibitor. In comparison to standard notch inhibitor, lead phytochemical showed two additional hydrophobic interactions with Ala80 and Leu81 amino acids. In conclusion, B. frutescens phytochemicals have cell cycle arrest, ROS production, apoptosis induction, and mitochondria membrane potential disruption efficacy in breast cancer cells. B. frutescens phytochemicals have the ability to downregulate the notch signaling pathway in triple-negative and luminal breast cancer cells.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Xanthorrhoeaceae/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
5.
Anticancer Res ; 39(8): 4043-4053, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366486

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is the most aggressive subtype, predominant in African American women. In this study, the antioxidant/anticancer activity of muscadine grape extracts and the role of their phenolic and flavonoid contents in exerting these properties were investigated in TNBC cells. MATERIALS AND METHODS: Berry extracts from muscadine genotypes were investigated for total phenolic content (TPC), total flavonoid content (TFC), antioxidant capacity, and anticancer effects using breast cancer cell lines, representing Caucasians and African Americans. RESULTS: The antioxidant activity was associated with high TPC content. Extracts showed cytotoxicity up to 78.6% in Caucasians and 90.7% in African American cells, with an association with high antioxidant capacity. There was a strong correlation between TPC and anticancer/antioxidant activities. CONCLUSION: The anticancer and antioxidant effects of muscadine grapes are attributed to the TPC of extracts, which showed a stronger positive correlation with growth inhibition of African American breast cancer cells compared to Caucasians.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitis/química , Afro-Americanos/genética , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Feminino , Flavonoides/química , Flavonoides/farmacologia , Frutas/química , Humanos , Células MCF-7 , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
Anticancer Res ; 39(8): 4149-4164, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366500

RESUMO

BACKGROUND/AIM: Signaling regulation of myeloid zinc finger 1 (MZF1) has been implicated in the progression of many human malignancies; however, the mechanistic action of MZF1 in triple-negative breast cancer (TNBC) progression remains elusive. In this study, the aim was to investigate the molecular mechanisms of MZF1 and its functional role in TNBC cellular migration and invasion. MATERIALS AND METHODS: Hs578T and MDA-MB-231 cells were transfected to stably express the acidic domain of MZF1 (MZF160-72), or were transfected with MZF1-specific or ELK1-specific short hairpin RNA (shRNA). Changes in cell morphology and distributions of cellular proteins were observed and subsequently migration and invasion were measured by wound healing and transwell assays. Expression levels of epithelial-mesenchymal transition (EMT)-related genes were carried out using immunoblotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR) assays. Data of transcriptional regulation were obtained from promoter-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: Herein, we found that MZF1 in high-level MZF1-expressing TNBC cells is associated with cell migration, invasion, and mesenchymal phenotype. MZF1 interacted with the promoter region of insulin-like growth factor 1 receptor (IGF1R) to drive invasion and metastasis of high-level MZF1-expressing TNBC cells. Exogenous expression of the acidic domain of MZF1 repressed the binding of endogenous MZF1 to IGF1R promoter via blocking the interaction with ETS-like gene 1 (ELK1). This blockage not only caused MZF1 protein degradation, but also restrained ELK1 nuclear localization in high-level MZF1-expressing TNBC cells. MZF1, but not ELK1, was necessary for the retention of mesenchymal phenotype by repressing IGF1R promoter activity in TNBC cells expressing high levels of MZF1. Activation of the IGF1R-driven p38MAPK-ERα-slug-E-cadherin signaling axis mediated the conversion of mesenchymal cell to epithelial phenotype, caused by MZF1 destabilization. These results suggest that MZF1 is an oncogenic inducer. CONCLUSION: Blocking of the MZF1/ELK1 interaction to reduce MZF1 protein stability by saturating the endogenous MZF1/ELK1 binding domains might be a promising therapeutic strategy for the treatment of high-level MZF1-expressing TNBC.


Assuntos
Fatores de Transcrição Kruppel-Like/genética , Receptores de Somatomedina/genética , Neoplasias de Mama Triplo Negativas/genética , Proteínas Elk-1 do Domínio ets/genética , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Transição Epitelial-Mesenquimal/genética , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Regiões Promotoras Genéticas/genética , Domínios Proteicos/genética , Transdução de Sinais/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética
7.
Oncol Rep ; 42(4): 1569-1579, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364749

RESUMO

Triple­negative breast cancer (TNBC) is characterized by fast progression with high potential for metastasis, and poor prognosis. The dysregulation of microRNAs (miRNAs) occurring in the initiation or progression of cancers often leads to aberrant gene expression. The aim of the present study was to explore the function of miR­126 in TNBC cells. Expression levels of miR­126­3p were determined by quantitative real­time PCR. Then, the effects of miR­126­3p on migration, proliferation, invasion, and angiogenesis were assessed through in vitro experiments including Cell Counting Kit­8, colony formation, Transwell invasion and vasculogenic mimicry formation assays. One of the target genes for miR­126­3p predicted by TargetScan was confirmed by luciferase activity assay. Results indicated that miR­126­3p expression was reduced in TNBC cell lines. Functional assays revealed that miR­126­3p overexpression inhibited cell proliferation, migration, invasion, colony formation capacity and vasculogenesis by 1.2­, 1.8­, 2.3­, 2.0­ and 3.3­fold, respectively, compared to the miRNA­negative control group of MDA­MB­231 cells (P<0.001, respectively). In addition, the regulator of G­protein signaling 3 (RGS3) was hypothesized and validated as a direct target of miR­126­3p in TNBC. The proliferation, migration, invasion, colony formation capacity and vasculogenesis of MDA­MB­231 cells were significantly increased by 1.4­, 2.0­, 1.8­, 1.4­ and 3.2­fold, respectively, in cells transfected with pcDNA3.0­RGS3 compared to pcDNA3.0­negative control groups (P<0.001, respectively). The influence of miR­126­3p expression was reversed by RGS3 restoration. Collectively, the present study revealed that miR­126­3p plays a role as a tumor suppressor in regulating TNBC cell activities by targeting RGS3, indicating that the miR­126­3p/RGS3 axis may be a potential treatment target.


Assuntos
MicroRNAs/genética , Proteínas RGS/genética , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , MicroRNAs/biossíntese , Invasividade Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Proteínas RGS/biossíntese , Proteínas RGS/metabolismo , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
8.
Biol Res ; 52(1): 38, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349873

RESUMO

BACKGROUND: Breast cancer is the second common malignant cancer among females worldwide. Accumulating studies have indicated that deregulation of miRNA expression in breast cancer will contribute to tumorigenesis and form different cancer subtypes. However, the reported studies on miR-29b-3p-regulated breast cancer are limited so far. Herein, we investigated the role and mechanism of miR-29b-3p in the triple negative breast cancer cell line MDA-MB-231. METHODS: The relative miR-29b-3p expression in different breast cancer cell lines were determined by qRT-PCR. CCK8 and colony formation assay were used to determine the influence of miR-29b-3p on cell proliferation. Migration assay and invasion assay were performed for cell migration and invasion respectively. To study the cell integrity immunofluorescence was performed. TUNEL assay, flow cytometry assay, hoechst staining and western blot were conducted to determine the influence of miR-29b-3p inhibitor on cell apoptosis. TRAF3 was found to be the target gene of miR-29b-3p using bioinformatics predictions. Dual-luciferase assay was performed to determine the relative luciferase activity in NC, miR-29b-3p mimic, miR-29b-3p inhibitor with TRAF3 3'-UTR wt or TRAF3 3'-UTR mt reporter plasmids. The proteins expression of NF-κB signaling pathway in MDA-MB-231 after transfection with NC, miR-29b-3p mimic, miR-29b-3p inhibitor were determined by western blot. RESULTS: The miR-29b-3p expression was significantly increased in MDA-MB-231 compare with MCF-10A. miR-29b-3p inhibitor reduced the cell viability of MDA-MB-231 and inhibited cell migration and invasion. Cell cytoskeleton integrity destroyed after miR-29b-3p inhibitor treatment. Furthermore, we identified the mechanism and found miR-29b-3p targets the TRAF3 and activates NF-κB signaling pathway. CONCLUSIONS: From the above studies, our results indicated that miR-29b-3p acts as a promoter for the development of MDA-MB-231.


Assuntos
Apoptose/efeitos dos fármacos , Regulação para Baixo/genética , MicroRNAs/metabolismo , Fator 3 Associado a Receptor de TNF/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Luciferases/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Neoplasias de Mama Triplo Negativas/patologia
9.
Eur J Med Chem ; 179: 694-706, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284080

RESUMO

Unique derivatives of androstene and estrane series containing N-sulfonylimidate pendants were prepared from 17α-ethynyl steroids via Cu-catalyzed azide-alkyne cycloaddition to tosyl azide in the presence of alcohols. The synthesized compounds were screened for cytotoxicity against human breast cancer cell lines and ERα agonist activity. The hit compound 3,17ß-dimethoxy-17α-[iso-propyl-2'-N-tosylacetimidate]estra-1,3,5(10)-triene (4n) had no ERα-mediated hormonal activity and was found to exhibit potent cytotoxic effect in an ERα-positive breast cancer cell line. N-Sulfonylimidate 4n displayed high antiproliferative potency against triple-negative MDA-MB-231 breast cancer cells, while it was non-toxic towards normal mammary epithelial cells. Compound 4n was found to alter activity of various signaling pathways (NF-κB, Slug, cyclin D1, ERK) supporting the growth and invasiveness of tumor cells.


Assuntos
Antineoplásicos/farmacologia , Imidoésteres/farmacologia , Esteroides/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidoésteres/síntese química , Imidoésteres/química , Células MCF-7 , Estrutura Molecular , Esteroides/síntese química , Esteroides/química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia
10.
Life Sci ; 232: 116678, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344429

RESUMO

AIMS: In this work, it was sought to determine if there was synergism between doxorubicin (DOX), a well-known antineoplastic, and sclareol (SC), a diterpene from natural origin, in breast cancer treatment. Moreover, it was investigated if their co-loading in the same nanocarrier would result in a gain of activity and/or a toxicity diminishment. MAIN METHODS: The synergism of the DOX:SC combination was evaluated in MDA-MB-231 and 4T1 cells. A nanostructured lipid carrier (NLC) co-encapsulating DOX and SC in their synergistic molar ratio was prepared and characterised, in terms of mean diameter, zeta potential, DOX encapsulation efficiency, small angle X-ray scattering, differential scanning calorimetry, and polarised light microscopy for further intravenous administration. The anticancer activity of the combination, free and encapsulated, was evaluated in 4T1-tumour bearing mice. KEY FINDINGS: It was determined that DOX:SC combination at the molar ratio 1:1.9 presents better synergistic anticancer activity than the molar ratio 1:7.5 in vitro. DOX:SC-loaded NLC (NLC-DOX-SC) improved in vitro cytotoxic and in vivo antitumour activity compared to free DOX. Although NLC-DOX-SC and free DOX:SC, at the synergistic molar ratio, showed similar activity in the in vivo study, the free combination provoked body weight loss, behaviour alterations and haematological toxicity in the animals, while this was not observed for NLC-DOX-SC. SIGNIFICANCE: This work shows that SC and DOX present synergistic anticancer activity for breast cancer treatment whereas NLC-DOX-SC was a feasible alternative to attain the benefits posed by DOX:SC combination but with none to fewer side effects.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Diterpenos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos , Lipídeos/química , Nanoestruturas/química , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C
11.
Nat Commun ; 10(1): 2983, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278301

RESUMO

Ttriple-negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype. Enhanced TNBC cell motility is a prerequisite of TNBC cell dissemination. Here, we apply an imaging-based RNAi phenotypic cell migration screen using two highly motile TNBC cell lines (Hs578T and MDA-MB-231) to provide a repository of signaling determinants that functionally drive TNBC cell motility. We have screened ~4,200 target genes individually and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, which are linked to signaling networks predictive for breast cancer progression. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF are essential for cancer cell migration, amplified in human primary breast tumors and associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF causes primarily down regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B is essential for TNBC metastasis formation in vivo, making PRPF4B a candidate for further drug development.


Assuntos
Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Matriz Extracelular/metabolismo , Feminino , Adesões Focais/genética , Humanos , Microscopia Intravital , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Processamento de RNA/genética , RNA Interferente Pequeno/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6/genética , Transdução de Sinais/genética , Análise de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade
12.
Anticancer Res ; 39(7): 3863-3869, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262914

RESUMO

BACKGROUND: Breast matrix-producing carcinomas (MPCs) are rare, and usually triple-negative (TNBC; i.e. oestrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor 2-negative). This study evaluated the clinical features, immunohistochemical profiles, and pathological response to neoadjuvant chemotherapy (NAC) of patients with MPCs. PATIENTS AND METHODS: Five MPCs were identified among 247 patients with TNBC receiving anthracycline- and taxane-based NAC. Pathological response was assessed using surgical specimens. RESULTS: All tumours were histological grade 3 according to pre-treatment core biopsies. Mean Ki-67 and p53 positivity were 65% and 90%, respectively. All tumours were TNBC, and epidermal growth factor receptor-, cytokeratin 5/6-, and vimentin-positive. Grade 3 (pathological complete response) was achieved in 0% (0/5) and 32% (77/242) of those with MPCs and with TNBCs of no specific histological type, respectively, and grade 1a (poor response) in 80% (4/5) and 13% (31/242), respectively. CONCLUSION: MPCs are basal-type TNBCs expressing epithelial-mesenchymal transition markers, with a poor response to standard NAC. Further studies are needed to improve the treatment of this rare but aggressive tumour.


Assuntos
Antineoplásicos/uso terapêutico , Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade
13.
Pan Afr Med J ; 33: 22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312338

RESUMO

Breast cancer is a complex disease characterized by the accumulation of multiple molecular alterations giving each tumor phenotype and an own evolutionary potential. This study aimed to describe the distribution of the profile and molecular subtypes of breast cancers followed at Surgical Oncology Unit of Donka National Hospital. This was retrospective and descriptive study on cases of breast cancer in which the hormone receptor status and expression of the Her2 oncogene have been performed from 2007 to 2016. We recorded 58 cases including 56 (96.6%) women and 2 (3.4%) men. The average age was 48.2 ± 10.9. Invasive ductal carcinoma accounted for 50 (86.2%) cases. The SBR grade was II in 31(53.4%) cases, III in 21 (36.2%) cases and I in 6 (10.3%) cases. The tumor was classified as T4 in 36 (62.1%) cases; it was metastatic in 11(19.0%) cases. Estrogen receptors were positive in 29 (50.0%) cases, progesterone receptors positive in 25 (43.1%) cases, the Her2 oncogene was positive in 22 (39.3%) cases. The distribution of molecular sub-types was: 20 (34.5%) luminal A, 15 (25.9%) triple negative, 13 (22.4%) Her2 overexpressed, 8 (13.8%) luminal B and 2 (3.2%) undetermined. This preliminary study showed the poor accessibility of immunohistochemistry for the molecular diagnosis of breast cancer in our country. Luminal A subtypes and triple negatives were more common. The determination of molecular subtypes is a rational basis for hormone therapy and targeted therapy, thus personalizing the treatment of breast cancer.


Assuntos
Neoplasias da Mama Masculina/patologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/genética , Carcinoma Ductal de Mama/epidemiologia , Feminino , Guiné/epidemiologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Receptor ErbB-2/genética , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/epidemiologia
14.
Chem Biol Interact ; 309: 108703, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31194954

RESUMO

ß-2-himachalen-6-ol (HC), a major sesquiterpene isolated from the Lebanese wild carrot umbels, was shown to possess remarkable in vitro and in vivo anticancer activities. The present study investigates the anti-metastatic activity of HC post 4T1 breast cancer cells inoculation in a murine model. The effect of HC on 4T1 cell viability was assessed using WST-1 kit, while cell cycle analysis was performed using flow cytometry. Tumor development and metastasis were evaluated by injecting 4T1 cells in the mice mammary gland region followed by either HC or cisplatin treatment. The 6-thioguanine assay was used for the quantification of metastatic cells in the blood. HC treatment caused a dose-dependent decrease in cell viability with IC50 and IC90 values of 7 and 28 µg/mL respectively. Concomitant treatment with cisplatin significantly reduced cell viability when compared to cells treated with cisplatin or HC alone. Flow cytometry revealed a significant increase (p˂0.05) in cell count in the Sub-G1 phase at HC 10 µg/mL, and total DNA fragmentation (p˂0.001) at HC 25 µg/mL. Annexin/PI staining showed early and late apoptotic mode of cell death upon treatment with HC. Histopathological evaluation revealed less incidence of primary and metastatic tumor/inflammation in the HC and cisplatin treated groups. Tumor size and colony-forming units were significantly decreased in the HC treated group. HC treatment induced cell cycle arrest, promoted apoptosis and reduced the incidence of primary and metastatic lesions caused by 4T1 cells. The present findings suggest that HC has an anti-metastatic potential against aggressive types of cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Sesquiterpenos/uso terapêutico , Pele/patologia , Transplante Homólogo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
15.
Anticancer Res ; 39(6): 3111-3119, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177156

RESUMO

BACKGROUND: The prognostic value of tumor-infiltrating lymphocytes (TILs) in curatively resected, but systemically untreated early-stage triple-negative breast cancer (TNBC) was investigated. MATERIALS AND METHODS: Patients with systemically untreated early TNBC between 1999 and 2012 were retrospectively reviewed. A low TIL level was defined as the presence of ≤10% stromal TILs Relapses were classified into locoregional and distant relapse. The primary endpoint was breast cancer-specific survival (BCSS). RESULTS: In 72 patients, the median TIL value was 10%, and low TIL status was found in 54.2%. Patients with pT1 and nodal-positive disease constituted 75% and 11.1%, respectively. With a median follow-up of 99 months, 26.4% patients experienced relapse; local in 63.2%, distant in 36.8%, and 9.7% died of disease progression. A low TIL level was significantly associated with distant relapse (p=0.013), and inferior 10-year BCSS, which was consistently observed in patients with T1a/b or N0 disease. CONCLUSION: A low TIL level seems to be an intrinsic prognostic factor in systemically untreated patients with early-stage TNBC, even in the T1a/bN0 subset.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Metástase Linfática , Contagem de Linfócitos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Seul , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgia , Adulto Jovem
16.
BMC Bioinformatics ; 20(1): 356, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238876

RESUMO

BACKGROUND: Breast and prostate cancers are typical examples of hormone-dependent cancers, showing remarkable similarities at the hormone-related signaling pathways level, and exhibiting a high tropism to bone. While the identification of genes playing a specific role in each cancer type brings invaluable insights for gene therapy research by targeting disease-specific cell functions not accounted so far, identifying a common gene signature to breast and prostate cancers could unravel new targets to tackle shared hormone-dependent disease features, like bone relapse. This would potentially allow the development of new targeted therapies directed to genes regulating both cancer types, with a consequent positive impact in cancer management and health economics. RESULTS: We address the challenge of extracting gene signatures from transcriptomic data of prostate adenocarcinoma (PRAD) and breast invasive carcinoma (BRCA) samples, particularly estrogen positive (ER+), and androgen positive (AR+) triple-negative breast cancer (TNBC), using sparse logistic regression. The introduction of gene network information based on the distances between BRCA and PRAD correlation matrices is investigated, through the proposed twin networks recovery (twiner) penalty, as a strategy to ensure similarly correlated gene features in two diseases to be less penalized during the feature selection procedure. CONCLUSIONS: Our analysis led to the identification of genes that show a similar correlation pattern in BRCA and PRAD transcriptomic data, and are selected as key players in the classification of breast and prostate samples into ER+ BRCA/AR+ TNBC/PRAD tumor and normal tissues, and also associated with survival time distributions. The results obtained are supported by the literature and are expected to unveil the similarities between the diseases, disclose common disease biomarkers, and help in the definition of new strategies for more effective therapies.


Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias da Próstata/genética , Transcriptoma , Neoplasias de Mama Triplo Negativas/genética , Estrogênios/metabolismo , Feminino , Redes Reguladoras de Genes , Humanos , Modelos Logísticos , Masculino , Análise de Componente Principal , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
17.
BMC Genomics ; 20(1): 452, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159741

RESUMO

BACKGROUND: Full RNA-Seq is a fundamental research tool for whole transcriptome analysis. However, it is too costly and time consuming to be used in routine clinical practice. We evaluated the transcript quantification agreement between RNA-Seq and a digital multiplexed gene expression platform, and the subtype call after running the PAM50 assay in a series of breast cancer patients classified as triple negative by IHC/FISH. The goal of this study is to analyze the concordance between both expression platforms overall, and for calling PAM50 triple negative breast cancer intrinsic subtypes in particular. RESULTS: The analyses were performed in paraffin-embedded tissues from 96 patients recruited in a multicenter, prospective, non-randomized neoadjuvant triple negative breast cancer trial (NCT01560663). Pre-treatment core biopsies were obtained following clinical practice guidelines and conserved as FFPE for further RNA extraction. PAM50 was performed on both digital multiplexed gene expression and RNA-Seq platforms. Subtype assignment was based on the nearest centroid classification following this procedure for both platforms and it was concordant on 96% of the cases (N = 96). In four cases, digital multiplexed gene expression analysis and RNA-Seq were discordant. The Spearman correlation to each of the centroids and the risk of recurrence were above 0.89 in both platforms while the agreement on Proliferation Score reached up to 0.97. In addition, 82% of the individual PAM50 genes showed a correlation coefficient > 0.80. CONCLUSIONS: In our analysis, the subtype calling in most of the samples was concordant in both platforms and the potential discordances had reduced clinical implications in terms of prognosis. If speed and cost are the main driving forces then the preferred technique is the digital multiplexed platform, while if whole genome patterns and subtype are the driving forces, then RNA-Seq is the preferred method.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Recidiva Local de Neoplasia/genética , Neoplasias de Mama Triplo Negativas/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Neoplasias de Mama Triplo Negativas/patologia
18.
Dokl Biochem Biophys ; 485(1): 104-106, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31201625

RESUMO

Reduced expression of metastatic marker protein S100A4 in triple-negative breast cancer cells MDA-MB-231 leads to a decrease in the migration ability of cells and increases the sensitivity of the modified cells to docetaxel therapy. Cells capable of migration differ from the immotile cells in the content of the S100A4 protein in the cell, and this difference persists after the treatment of cells with the agents that reduce the intracellular level of S100A4. The presence of exogenous S100A4 protein in culture medium reduces the content of this protein in breast cancer cells. The results of the study show that the ability of breast cancer cells to migrate depends on the S100A4 protein concentration in the cell.


Assuntos
Movimento Celular , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Proteína A4 de Ligação a Cálcio da Família S100/biossíntese , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Proteínas de Neoplasias/genética , Proteína A4 de Ligação a Cálcio da Família S100/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
19.
Int J Nanomedicine ; 14: 3645-3667, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190817

RESUMO

Background: Neo-adjuvant chemotherapy is an effective strategy for improving treatment of breast cancers. However, the efficacy of this treatment strategy is limited for treatment of triple negative breast cancer (TNBC). Gene therapy may be a more effective strategy for improving the prognosis of TNBC. Methods: A novel 25 nucleotide sense strand of miRNA was designed to treat TNBC by silencing the Slug gene, and encapsulated into DSPE-PEG2000-tLyp-1 peptide-modified functional liposomes. The efficacy of miRNA liposomes was evaluated on invasive TNBC cells and TNBC cancer-bearing nude mice. Furthermore, functional vinorelbine liposomes were constructed to investigate the anticancer effects of combined treatment. Results: The functional miRNA liposomes had a round shape and were nanosized (120 nm). Functional miRNA liposomes were effectively captured by TNBC cells in vitro and were target to mitochondria. Treatment with functional liposomes silenced the expression of Slug and Slug protein, inhibited the TGF-ß1/Smad pathway, and inhibited invasiveness and growth of TNBC cells. In TNBC cancer-bearing mice, functional miRNA liposomes exerted a stronger anticancer effect than functional vinorelbine liposomes, and combination therapy with these two formulations resulted in nearly complete inhibition of tumor growth. Preliminary safety evaluations indicated that the functional miRNA liposomes did not affect body weight or cause damage to any major organs. Furthermore, the functional liposomes significantly increased the half-life of the drug in the blood of cancer-bearing nude mice, and increased drug accumulation in breast cancer tissues. Conclusion: In this study, we constructed novel functional miRNA liposomes. These liposomes silenced Slug expression and inhibited the TGF-ß1/Smad pathway in TNBC cells, and enhanced anticancer efficacy in mice using combined chemotherapy. Hence, the present study demonstrated a promising strategy for gene therapy of invasive breast cancer.


Assuntos
Inativação Gênica , MicroRNAs/metabolismo , Nanopartículas/química , Tamanho da Partícula , Fatores de Transcrição da Família Snail/genética , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Lipossomos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
20.
J Exp Clin Cancer Res ; 38(1): 187, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072371

RESUMO

BACKGROUND: Current prognostic tools and targeted therapeutic approaches have limited value for metastatic triple negative breast cancer (TNBC). Building upon current knowledge, we hypothesized that epoxyeicosatrienoic acids (EETs) and related CYP450 epoxygenases may have differential roles in breast cancer signaling, and better understanding of which may uncover potential directions for molecular stratification and personalized therapy for TNBC patients. METHODS: We analyzed the oxylipin metabolome of paired tumors and adjacent normal mammary tissues from patients with pathologically confirmed breast cancer (N = 62). We used multivariate statistical analysis to identify important metabolite contributors and to determine the predictive power of tumor tissue metabolite clustering. In vitro functional assays using a panel of breast cancer cell lines were carried out to further confirm the crucial roles of endogenous and exogenous EETs in the metastasis transformation of TNBC cells. Deregulation of associated downstream signaling networks associated with EETs/CYPs was established using transcriptomics datasets from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Comparative TNBC proteomics using the same tissue specimens subjected to oxylipin metabolomics analysis was used as validation set. RESULTS: Metabolite-by-metabolite comparison, tumor immunoreactivity, and gene expression analyses showed that CYP epoxygenases and arachidonic acid-epoxygenation products, EET metabolites, are strongly associated with TNBC metastasis. Notably, all the 4 EET isomers (5,6-, 8,9-, 11,12-, and 14,15-EET) was observed to profoundly drive the metastasis transformation of mesenchymal-like TNBC cells among the TNBC (basal- and mesenchymal-like), HER2-overexpressing and luminal breast cancer cell lines examined. Our pathway analysis revealed that, in hormone-positive breast cancer subtype, CYP epoxygenase overexpression is more related to immune cell-associated signaling, while EET-mediated Myc, Ras, MAPK, EGFR, HIF-1α, and NOD1/2 signaling are the molecular vulnerabilities of metastatic CYP epoxygenase-overexpressing TNBC tumors. CONCLUSIONS: This study suggests that categorizing breast tumors according to their EET metabolite ratio classifiers and CYP epoxygenase profiles may be useful for prognostic and therapeutic assessment. Modulation of CYP epoxygenase and EET-mediated signaling networks may offer an effective approach for personalized treatment of breast cancer, and may be an effective intervention option for metastatic TNBC patients.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Ácido Eicosapentaenoico/genética , Metaboloma/genética , Oxilipinas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Ácido Araquidônico/genética , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Feminino , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Transdução de Sinais/genética , Nanomedicina Teranóstica , Neoplasias de Mama Triplo Negativas/patologia
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